Preparation of 13-alkylgona-1,3,5(10),8,14-pentaenes



United States Patent 3,478,106 PREPARATION OF 13-ALKYLGONA-1,3,5(10),8,14- PENTAENES Gordon Alan Hughes, Haverford, Pa., and Herchel Smith, 500 Chestnut Laue, Wayne, Pa. 19087; said Hughes assignor to said Smith Original application Sept. 27, 1967, Ser. No. 670,982. Divided and this application Nov. 18, 1968, Ser. No. 776,600

Int. Cl. C07c 171/07, 167/02 US. Cl. 260--590 7 Claims ABSTRACT OF THE DISCLOSURE This application is a division of co-pending application Ser. No. 670,982 filed Sept. 27, 1967, now abandoned, which is a continuation-in-part of co-pending application Serial No. 461,908, filed June 7, 1965; which is a division and continuation-in-part of co-pending application Ser. No. 228,384 filed Oct. 4, 1962; which is a continuation'inpart of application Ser. No. 196,557 filed May 16, 1962, now abandoned.

This invention relates to compositions of matter classified in the art of chemistry as substituted unsaturatedgonane derivatives, to intermediates therefor, and to processes for making and using such compositions.

In describing the invention, reference will be made in the following specification to the annexed drawings wherein:

FIGURE 1 illustrates schematically the sequence of reactions for preparaing a 13-alkylgona-1,3,5(10),8,l4- pentaene from a tetralone and a 1,3-cycloalkanedione having at least one hydrogen at the 2-position, specifically 13B-ethylgona-1,3,5 (10),'8,14 pentaen 17 one from 6- methoxy-l-tetralone and 2-ethyl-1,3-cyclopentanedione.

FIGURE 2 illustrates schematically the cyclization of a 2-alkyl-2- [2- l,2,3,4-tetrahydro- 1 -naphthylidene) ethyl] 1,3-cyclopentanedione to prepare a 13alkylgona-1,3,5- (lO),8,l4,16-hexaene, specifically 2-ethyl-2 [2 (6 -methoxy-l,2,3,4-tetrahydro-1-naphthylidene)ethyl] 1,3 cyclopentanedione to 17-acetoxy-l3-ethyl-3-methoxygona- 1,3,5(10),8,14,16-hexaene.

The invention sought to be patented, in a principal composition aspect, is described as residing in the concept of the 8,14-secogona-l,3,5(10),9(11)-tetraen-l4-one nucleus having attached thereto in the l3-position a monovalent polycarbonalkyl radical (FIGURE 1, IV).

The tangible embodiments of the composition aspect of the invention possess the inherent general physical properties of being viscous gums of low melting 120") white crystalline solids, are substantially insoluble in 3,478,106 Patented Nov. 11, 1969 water, and are generally soluble in polar solvents such as dimethylacetamide. Examination of compounds produced according to the hereinafter described process reveals, upon ultraviolet and infrared spectrographic analysis, spectral data supporting the molecular structures herein set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials and the mode of synthesis, confirm the structure of the compositions sought to be patented.

The tangible embodiments of said composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity as evidenced by standard test procedures. Such compositions show estrogenic and blood lipid lowering effects, and these findings indicate their usefulness in the treatment of female hypogonadism, amenorrhea, dysmenorrhea, ovulation block, functional uterine bleeding, acne, arteriosclerosis, osteoporosis, hormone dependent tumors, infertility, and in contraception. In particular, it has been established that alterations of the natural steroid structure made possible by our discovery result not merely in a change of degree of hormonal activity but, as a result of the separation of types of hormonal activity, alter in an unexpected way its basic nature so that a desirable hormone eflect is maximized and an undesirable hormone effect is minimized.

In addition to their inherent applied use characteristics, the compositions of this invention are useful in practicing the process aspect of the present invention in the making of the gonane compositions herein described according to the sequence of reactions described herein.

The invention sought to be patented, in a principal process of making the compositions aspect, as illustrated in annexed FIGURE 1 is described as residing in the concept of a sequence of reactions including reacting a compound having a l-tetralone nucleus (I) with a vinyl Grignard reagent to obtain a compound with a l-vinyltetral-lol nucleus (II); condensing said tetralol with a compound with a" '1,3-cyclopentanedione nucleus having attached thereto in the 2-position a monovalent polycarbonalkyl radical, to obtain a compound with a 2-[2-(1,2,3,4-tetrahydro-l-naphthylidene)ethyl]-1,3 cyclopentanedione nucleus having attached to the 2-position of the cyclopentane a monovalent polycarbon-alkyl radical (IV); eyclizing under acid reaction conditions to obtain a compound with a gona-l,3,5(l0),8,14-pentaen-l7-one nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (V).

The invention sought to be patented in a second process aspect is described as residing in the concept of cyclizing a compound having a 2-alkyl-2-[2-(1,2,3,4-tetrahydrol-naphthylidene)ethyl]-l,3-cyclopentanedione nucleus under anhydrous acid conditions in the presence of certain enol-alkylating or enolacylating reagents to form a 13- alkylgona-l,3,5(l0),8,l4,l6-hexane (FIGURE 2, VI).

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

Referring now to FIGURE 1 wherein the compounds are assigned roman numerals for identification schematically, the sequence of reactions involved in the synthesis 3 of a specific embodiment, namely 13f1-ethyl-3-methoxy 8,14-secogona-1,3,5(),9(11)-tetraene-14,17 dione, and the reaction involved in the use of said unsaturated secogonane to prepare a 13-alkylgona-1,3,5(l0),8,l4- pentaene, specifically l3fi-ethyl-3-methoxygona-1,3,5(10), 8,14-pentaen-17-one, is illustrated.

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

6-methoxy-1-tetralone (I) is treated with vinyl magnesium chloride or vinyl magnesium bromide in tetrahydrofuran to form 6-methoxy-l-vinyl-l-tetralol (II). This tetralol (II) is then reacted with 2-ethyl-1,3-cyclopentanedione (III) under Michael condensation conditions, e.g., refluxing in methanolic potassium hydroxide, to form 2- ethyl-2-[2-(6-methoxy 1,2,3,4 tetrahydro 1 naphthylidene)ethyl]-1,3-cyclopentanedione (IV). Compound IV is then cyclodehydrated, preferably at the reflux temperature of a solvent, such as ethanol, in the presence of a dehydrating acid, preferably hydrochloric acid, to effect ring closure to give the tetracyclic compound 13fl-ethyl-3- methoxygona-1,3,5 10) ,8, 14-pentaen-17-one (V).

The aromatic ring of the tetralone (FIGURE 1, I) used as the starting material for the preparation of the compositions and initial preparations of the invention may be unsubstituted or have one or more substituents. In order not to deactivate the position for subsequent ring closure, the substituents (if any) must include a para-directing group (referring to electrophilic aromatic substitution) such as alkoxy, or alkylamine, and the group may be present initially or may be introduced later but before ring closure, either directly, or by conversion from a meta-directing group such as nitro.

The term para-directing group (referring to electrophilic aromatic substitution) as used herein means an activating group such as those hereinbefore listed and which activate all positions on the aromatic nucleus. Thus, if the group is para-directing, as defined above, it can be in a position meta to the ortho position to which ring closure is limited by steric considerations, said position being activated even though another position is more highly activated. Ring closure could not occur at the said more highly activated position because of the abovementioned steric limitations. For the processes of the invention and except for the limitations expressed in this specification, variations of the substituents on the A-ring of the fully formed tetracyclic structures, or the intermediates leading thereto, are full equivalents of each other.

The carbon atoms at positions 3 and 4 of the starting tetral-l-one (I) can be substituted, as, for example, with an alkyl group such as methyl or ethyl. These substituents will appear in the 8,14-seco structures of the invention at the 7 and 6-positions respectively.

For the processes of the invention and except for the limitations expressed in this specification, variations of the B-ring on the fully formed tetracyclic structures, or on the intermediates leading thereto, are full equivalents of each other.

In the step involving condensation of the vinyl tetralol, the nucleophilic compound is a cyclopentane-1,3-dione which is mono-substituted at the 2-position. By varying the group at the 2-position of the cyclopentane-1,3-dione, the invention provides a way to produce compounds resembling natural steroids save at the 13-position. The starting materials for the preparation of the 2-substituted 1,3-cyclopentanediones are ketones of the structure RCH COCH where R is the substituent which will appear at the 2-position of the 1,3-cyclopentanediones.

The starting ketone is reacted with diethyl oxalate in the presence of base to form a cyclopentane-1,3,4-trione- S-glyxolic ester substituted at position 2 with the group R represent in the starting ketone. The product is treated wi h ac d to r move the -subStituen and the 4-ketone function is then removed by Wollf-Kishner reduction, involving selective semicarbazone formation at C and heating the product with base such as sodium hydroxide. On acidification the required 2-substituted-l,3-cyclopentanedione can be isolated. Thus, the group R, which eventually forms the 2-substituent of the 1,3-cyclopentanedione, can be any organic group which is stable to acid and to Wolff-Kishner conditions and can be methyl, ethyl, propyl, cetyl, diethylaminoethy'l, etc. Thus, alkyl groups of varying chain length such as, for example, ethyl, isopropyl, cetyl etc., may be introduced to form the gonane correspondingly substituted at the 13-position. Further, gonanes may be prepared wherein the l3-position is substituted with any organic radical. Thus, but without limiting the generality of the foregoing, an aralkyl or cycloalkylalkyl, bearing an hydroxy, amino, or alkylamino-substituent can readily be placed in the 13-position, and from such compounds other variations of the 13-position substituent can be prepared, as halo alkyl from hydroxyalkyls, or quaternary salts, amides, alkenyls, etc., from aminoalkyls.

For the processes of the invention and except for the limitations expressed in this specification, variations at the 13-position of the fully formed tetracyclic structures or on the intermediates leading thereto are the full equivalents of the claimed l3-position polycanbon-alkyl substituents, having pharmacological activity of the same type.

It will be apparent that the keto groups of the 8,14- secogona-1,3,5(10),9(11)-tetraene 14,17 dione nucleus can be reduced to hydroxy. Selective reduction of one of the two keto groups (which are equivalent) can be achieved by conventional means such as by treating with sodium borohydride as described by E. Elisberg, H. Vanderhaege and T. E. Gallagher, J. Amer. Chem. Soc., 74, 2814 (1952), and D. K. Fukushima and S. Dobriner, J. Org. Chem., 26, 3022 (1961), or with lithium aluminum tritertiary butoxyhydride as described by J. A. Zderic and I. Iriarte, J. Org. Chem., 27, 1756 (1962).

For the processes of the invention and except for the limitations expressed in this specification, modifications of one of the keto groups in the 8,14-se'cogona-14,17-dione structures are full equivalents of the claimed 8,10-secogona-1,3,5(10),9(11)-tetraene-l4,17-diones.

The specific reactions involved in the process of the invention will now be considered, as follows, reference being made to the drawings for typifying compounds:

The vinyl tetralol (II) is condensed with a nucleophilic compound under Michael reaction conditions. Thus the condensation can be carried out by bringing the two reagents together in solution in the presence of a base, for example, pyridine, triethylamine, diethylamine, sodium hydroxide, sodium methoxide or sodium hydrogen carbonate, and heating as required. The nature and amount of base employed in the condensation reaction will depend on the particular reagents used. Suitable solvents are hydrocarbons, such as benzene, and anhydrous alcohols, such as methanol.

As hereinbefore' noted, cyclodehydration of the C-ring is carried out under acidic conditions. Suitable are strong acids such as sulfuric, hydrochloric, p-toluenesulfonic, formic, etc., in such solvents as benzene, toluene, cyclohexane, anhydrous alcohol, etc. or by mixtures thereof. The preferred treatment is with methanolic hydrochloric acid at room temperature or at reflux. As hereinbeiore noted, it has been found that the ease of C-ring closure of the compounds of the invention to form tetracyclic compounds is affected by the nature of the substitutent on the preformed aromatic A-ring, and that subsequent cyclization is easier to carry out when the preformed aromatic A-ring contains a substitutent which activates the position at which cyclization is to occur. Where a compound is to be used directly for C-ring closure, it will in practice he one containing such a substituent. Those substituents which cause subsequent C-ring closure to occur readily are substituents which are groups that in electrophilic aromatic substitution activate an aromatic ring and are predominantly oand p-directing: for example, the hydroxy or alkoxy group.

When the C-ring closure is carried out in the presence of acylating agents such as isopropenyl acetate, cyclization of the C-ring is accompanied by the enol-acylation of the remaining keto-ne and the product is a 13-alkylgona- 1,3,5(),8,14,16-hexane' 17-ester (FIGURE 2, IV). When the cyclization is carried out in the presence of an alcohol and a trialkylorthoformate, the product is a 13- alkylgona-1,3,5(10),8,14,16-hexaen-17-ether.

While the tetracyclic compounds in this specification and the appended examples are named to describe the configuration to that of the natural steroids, it is to be understood that unless otherwise indicated, the product of each of the given manipulative procedures is a racemic mixture which contains said named compound and its enantiomorph.

EXAMPLE 1 3-methoxy-13/8-methyl-8,14-secogona-1,3,5( 10) ,9 l 1 tetraene-14,17-dione Add 1-vinyl-6-methoxy-l-tetralol (14 g.) to 2-methylcyclopentane-1,3-dione (10 g.) in methanol (40 cc.) containing potassium hydroxide (50 mg.) and reflux the mixt-ure for 5 hours. Evaporate the reaction mixture to a small bulk and add ether (200 cc.). Wash the ethereal solution with water, aqueous sodium carbonate, brine and dry. Evaporate the solvent and crystallize from ethanol to obtain the title product, M.P. 77-78"; UV: 267 m (6 18,000).

To obtain 13B-ethyl-3-methoxy-8,14-secogona-1,3,5 (10), 9(11)-tetraene14,l7-dione, treat 1-vinyl-6-methoxy-l-tetralol with Z-ethylcyclopentane-l,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13/i-n-propyl-3-methoxy-8,14-secogona-1,3,5 (10) ,9 11)-tetraene-14,17-dione, treat 1-vinyl-6-methoxyl-tetralol with Z-n-propylcyclopentane-l,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13/3-n-butyl-3-methoxy-8,14-secogona-l,3,5 10),9( 11)-tetraene-14,l7-dione, tre'at 1-vinyl-6-methoxyl-tetralol with 2-n-butylcyclopentane-1,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13,8-methyl-3-ethoxy-8,14-secogona-1,3,5 (10), 9(11)-tetraene-l4,17-dione, treat 1-vinyl-6-ethoxyl-tetralol with Z-methylcyclopentane-l,3-dione' and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13,3-ethyl-3-ethoxy-8,14-secogona-1,3,5(10), 9(11)-tetraene 14,17 dione, treat 1 vinyl 6 ethoxyl-tetralol with 2-ethylcyclopentane-1,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13fi-n-propyl-3-ethoxy-8J4-secogona-1,3,5 (10),9(1l)-tetraene-l4,17-dione, treat 1-vinyl-6-ethoxy-ltetralol with 2-n-propylcyclopentane-l,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13 3-n-butyl-3-ethoxy-8,14-secogona-1,3,5 10),9(11)-tetraene-l4,l7-dione, tre'at 1-vinyl-6-ethoxy-1- tetralol with 2-n-butylcyc1opentane-1,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13/3 ethyl 8,14 secogona 1,3,5(10),9 (11)-tetraene-14,17-dione, treat l-vinyl-l-tetralol with 2- ethylcyclopentane-l,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13/3-n-propyl-8,l4-secogona-1,3,5(10),9(11)- tetracne-14,17-dione, treat 1-vinyl-1-tetralol with 2-npropylcyclopentane-1,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13fi-ethyl-3-hydroxy-8,14-secogona-1,3,5(10), 9(11)-tetraene-14,17-dione, treat 1-vinyl-6-hydroxy-1-tetralol with Z-ethylcyclopentane-1,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13fl-ethyl-3-methoxy-6-methyl-8,14-secogona- 1,3,5 10) ,9 1 1 )-tetraene-14, 17-dione, treat 1-vinyl-6-methoxy-4-methyl-l-tetralol with Z-ethylcyclopentane-l,1- dione and methanolic potassium hydroxide according to the manipulative procedure described above.

To obtain 13 3 ethyl 3 methoxy 7 methyl 8,14 secogona 1,3,5(10),9(11) tetraene 14,17 dione, treat 1 vinyl 6 methoxy 3 methyl 1 tetralol with 2- ethylcyclopentane-l,3-dione and methanolic potassium hydroxide according to the manipulative procedure described above.

EXAMPLE 2 13,8-ethyl-3-methoxy-8,14-secogona-1,3,5(10),9(11)- tetraene-14,17-dione Add 6 methoxy 1 vinyl 1 tetralol (112 g.) to a suspension of Z-ethylcyclopentane-1,3-dione g.) in methanol (275 cc.) containing potassium hydroxide (0.3 g.). Reflux the mixture for 6 hours, concentrate to small volume and add benzene (400 cc.) and ether (400 cc.). Wash the organic solution with dilute aqueous sodium hydroxide, Water and brine, and evaporate the solvent. Recrystallize from methanol to obtain the title compound g.). Purify by further recrystallization from methanol; M.P. 65-67"; ultraviolet absorption maximum at 266 mu. (6 17,000).

Analysis.-Calculated for C H O C, 80.01%; H 9.41%. Found: C, 80.2%; H, 9.21%.

EXAMPLE 3 3-benzyloxy-13/3-methyl-8,14-secogona-1,3,5(10),9(11)- tetraene-l4,17-dione Reflux 6-hydroxy-1-tetralone (4 g.) in Water (10 cc.) and methanol (1 cc.) with benzyl chloride (3.1 g.) and sodium hydroxide (1 g.) for 2 hours. Add water to the cooled reaction mixture and isolate the product by extraction with ether and benzene. Dissolve the residue in benzene, filter through a column of alumina and recrystallize the product from cyclohexane to obtain 6-benzyloxy-l-tetralone (3.2 g.), M.P. 9 6-99.

Dissolve the above benzyl ether (3.1 g.) in tetrahydrofuran (15 cc.) and add the solution to vinyl magnesium chloride (from magnesium 1.44 g.) in tetrahydrofuran (200 cc.) and stir for 5 hours. Pour into saturated aqueous ammonium chloride and isolate the product by means of tztghgr t3) obtain 6-benzyloxy-l-vinyl-l-tetralol as a gum Reflux this vinyl ether (3 g.) and Z-methylcyclopentane-1,3-dione (1.5 g.) with 0.12% methanolic potassium hydroxide (25 cc.) for 5 hours. Evaporate most of the solvent, add water and extract the mixture with etherbenzene. Wash, dry and evaporate the organic solution and chromatograph the residue on Florex eluting with a mixture of benzene and hexane. Evaporate the eluate to obtain the title compound as a gum (1 g.); infrared absorption peaks at 2.75, 6.2, 6.7g.

EXAMPLE 4 3-benzyloxy-13fi-ethyl-8,14-secogona- 1,3,5 10) ,9 1 1 tetraene-14,17-dione Reflux 6 benzyloxy 1 vinyl 1 tetralol (3.2 g.) and 2 ethylcyclopentane 1,3 dione (1.5 g.) with 0.12% methanolic potassium hydroxide (25 cc.) for 5 hours. Evaporate most of the solvent under reduced pressure, add water and isolate the product with ether and benzene. Chromatograph the product on Florex and recrystallize the solid fractions from ether-methanol to obtain the title compound (0.8 g.), M.P. 64-67; infrared absorption peaks at 5.75, 6.2, 6.71.4.

Analysis.-Calculated for C H O C, 80.5%; H, 7.2%. Found: C, 80.4%; H, 7.3%.

EXAMPLE 5 13fi-methyl-3-tetrahydropyranyloxy-8, l4-secogona- 1,3,5() ,9 (1 1 -tetraene-14,17-dione Keep 6-hydroxy-1-tetralone (4 g.) for 3 days at room temperature in a mixture of dihydropyran cc.) and tetrahydrofuran (10 cc.) containing 2 drops of 10 N hydrochloric acid. Pour the mixture into aqueous sodium hydrogen carbonate and isolate the product by means of ether. Recrystallize from methanol to obtain 6-tetrahydropyranyloxy-l-tetralone (5.5 g.), M.P. 9193. Keep this material with vinyl magnesium chloride (from magnesium 1.42 g.) in tetrahydrofuran cc.) for 16 hours and then add ice-cold aqueous ammonium chloride and extract the mixture with ether. Wash and dry the ethereal solution and evaporate to give 6-tetrahydropyranyloxy-l-vinyl-ltetralol (6.1 g.) as a gum; infrared absorption peaks at 2.95, 6.1 and 6.05;.

Reflux the above pyranyl ether (6.1 g.) with 2-methyl cyclopentane-1,3-dione (3 g.) in methanol (50 cc.) containing potassium hydroxide (0.06 g.) for 8 hours. Concentrate the mixture, add ether (50 cc.) and benzene (50 cc.) and Wash the solution with 10% aqueous sodium hydroxide, Water, and brine. Evaporate to obtain the title compound as a gum (7.1 g.); ultra-violet absorption maximum at 270 m (6 10,200); infrared absorption peaks at 2.0, 5.8, 625p.

EXAMPLE 6 135-ethyl-8,14-secogona-1,3,5(l0),9(11)-tetraen- 14,17-dione Add a-tetralone (28 g.) in ether (100 cc.) to a stirred solution of vinyl magnesium chloride (from magnesium 12 g.) and vinyl chloride (32 g.) in tetrahydrofuran (300 cc.) at 18 and allow to warm to and keep for 18 hours with stirring. Pour onto ice and ammonium chloride and isolate the product with ether to give l-vinyl-ltetralol as a viscous oil g.). To this oil (5 g.) add 2- ethylcyclopentane 1,3-dione (5 g.) and potassium hydroxide (0.15 g.) and heat the mixture under nitrogen at 150 for 2 hours. To the cooled product add methanol and water and isolate the product with ether to give the title compound as a gum (5 g.); ultraviolet absorption maximum 257 mg (6 14,500); infrared absorption peaks at 5.7, 5.8g.

EXAMPLE 7 2,3-dimethoxy-l3fl-methyl-8,14-secogona-1,3,5 10) ,9 11)-tetraene-14,17-dione Dissolve 6,7-dimethoxy-l-tetralone (6.1 g.) in tetrahydrofuran cc.) and add the solution to 400 cc. of 2 molar vinyl magnesium chloride in tetrahydrofuran at room temperature. Let stand for 4 hours and pour into saturated ammonium chloride solution. Extract with ether, wash with water, dry and evaporate to obtain 1,2,3,4- tetrahydro-6,7-dimethoxy 1 vinyl-l-naphthol. Dissolve this product in methanol (30 cc.) and add the solution to 2-methylcyclopentane-1,3-dione (4 g.) in methanol (5 cc.) containing a trace of potassium hydroxide. Reflux for 3 hours, cool, pour into water and extract with ether. Wash the ethereal extracts with aqueous sodium bicarbonate and water, dry and evaporate the solvent and recrystallize the residue from methanol to obtain the title compound (5.45 g.), M.P. 104106.

Analysis.--Calculated for C H O C, 73.12%; H, 7.37%. Found: C, 73.37%; H, 7.14%.

EXAMPLE 8 3-cyclopentyloxy-13fl-ethyl-8,14-secogona 1,3,5(10),9(11)-tetraene-14,17-dione Dissolve 6-hydroxy-1-tetralone (16.2 g.) and sodium hydroxide (4 g.) in water (20 cc.) and ethanol (100 cc.)

and add cyclopentyl bromide (21 g.). Heat the mixture under reflux for 16 hours, evaporate to dryness, cool, add water and extract with ether. Wash the ethereal solution with 2 N sodium hydroxide, water and dry. Evaporate the solvent and distil to obtain 6-cyclopentyloxy-l-tetralone (9.8 g.), B.P. l63l65/0.4 mm.

Dissolve 6-cyclopentyloxy-l-tetralone (8.6 g.) in tetrahydrofuran (30 cc.) and add the solution to 40 cc. of vinyl magnesium bromide (from magnesium 1.95 g.) and vinyl bromide (6.5 cc.) in tetrahydrofuran at 25 Let stand for 4 hours and pour into saturated ammonium chloride solution. Extract with a mixture of ether and benzene and wash, dry and evaporate to obtain 1,2,3,4- tetrahydro-6-cyclopentyloxy-1-vinyl-l-naphthol as an oil (9.45 g.). Dissolve this product in methanol cc.) and add the solution to 2-ethylcyclopentane-1,3-dione (5 g.) in methanol (5 cc.) containing potassium hydroxide (0.1 g.). Reflux for 6 hours, cool, pour into water and extract with ether.-Wash and dry the ethereal solution and evaporate the solvent to obtain the title compound as an oil (11.8 g.); ultraviolet absorption at 267 my. (e 18,050).

EXAMPLE 9 13fl-ethyl-3-methoxy-7-methyl-8,14-secogona- 1,3,5(10),9(11)-tetraene-14,17-dione Stir 3-(m-methoxyphenyl)-2-methyl acrylic acid (1.5 g.) with stannic chloride (2 cc.) at 100 for 1 hour. Cool, add water and extract with ether. Wash, dry and evaporate the organic solution to obtain 6-methoXy-3-methyl-1- tetralone (1 g.), M.P. 70 (from ether-light petroleum).

Add a solution of 6-methoxy-3-methyl-l-tetralone (2.5 g.) in tetrahydrofuran (15 cc.) to a 3 molar solution of vinyl magnesium chloride in tetrahydrofuran (12 cc.) over a period of 30 minutes. Stir for 1 /2 hours and pour the reaction mixture into a mixture of aqueous ammonium chloride (10 cc.) and crushed ice (10 g.). Extract the mixture with ether-benzene and wash, dry and evaporate the organic solution to obtain 6-methoxy-3-methyl-l-vinyll-tetralol as a brown oil (2.9 g.). Add this alcohol (2.9 g.) to a solution of 2-ethylcyclopentane-1,3-dione (1.6 g.) in methanol (6 cc.) containing potassium hydroxide (0.01 g.) and reflux the mixture for 6 hours. Cool and filter the solution and add enough methanol to dissolve the precipitated oil. Cool in a Dry Ice-acetone bath and filter the precipitate. Recrystallize from methanol to obtain the title compound, M.P. 7980 (2.0 g.); ultraviolet absorption at 267 m (a 18,600).

Analysis.-Calculated for C H O C, 77.27%; H, 8.03%. Found: C, 77.09%; H, 8.07%.

EXAMPLE 10 13 fl-ethyl-3-tetrahydropyranyloxy-8, l4-secogona- 1,3,5 10) ,9 1 1 -tetraene- 14,17-dione Reflux 6-tetrahydropyranyloxy-l-vinyl-l-tetralol (69.5 g.) with 2-ethylcyclopentane-1,3-dione (75 g.) in 0.12% methanolic potassium hydroxide (500 cc.) for 6 hours. Evaporate to small bulk and add ether (200 cc.) and benzene (200 cc.). Wash the solution with 5% aqueous sodium hydroxide, water and brine and dry. Evaporate the solvent to obtain the title compound (59 g.).

EXAMPLE 11 17-hydroxy-3-methoxy-13,9-methyl-8,14-secogona- 1,3,5 (10) ,9 1 1 -tetraen- 14-one Dissolve 3 methoxy 13 8-methyl-8,14-secogona-l,3,5 (l0),9(11)-tetraene-14,17-dione (0.5 g.) in tetrahydrofuran (8 00.), methanol (8 cc.) and water (2 00.). Add sodium borohydride (0.2 g.) and stir for 3 minutes at 25. Add water and extract with ether. Wash, dry and evaporate the organic solution to give the title compound as a gum (0.49 g.). This compound can be acylated with an acyl halide in pyridine and the product cyclized with p-toluenesulfonic acid in benzene to 17-acyloxy-3-methoxy-13B- methylgona-l,3,5(10), 8,14-pentaene.

9 EXAMPLE 12 17-hydroxy-3-methoxy-l3{3-methyl-8,14?secogona- 1,3,5 10) ,9 1 1 -tetraen-14-one Dissolve 3 methoxy 13B-methyl-8,l4-secogona-1,3,5 (10),9(l1)-tetraen-14,l7-di0ne (5 g.) in tetrahydrofuran (100 cc.) and stir with lithium aluminum tritertiarybutoxyhydride (5 g.) for 20 hours. Add water and ammonium chloride, filter and dilute the filtrate with benzene and wash with water and brine and dry. Evaporate the solution to obtain the title compound (4.88 g.) as a gum.

EXAMPLE 13 3-m ethoxy-13fi-mehyl-8,l4-secogona- 1,3,5(),9(11)-tetraene-14,17-dio1 Reflux 3 methoxy 13/3 mehyl-S,14-secogona-l,3,5 (10) ,9(11)-tetraene-14,17-dione (2 g.) in tetrahydrofuran 100 cc.) with lithium aluminum hydride (1 g.) for 2 hours. Decompose excess reducing agent by adding ethyl acetate, then add water and extract with ether. Wash, dry andevaporate the organic solution to obtain the title compound as a gum (2 g.). Distil at 200 (bath) 10.2 mm. to obtain a pure sample.

Analysis-Calculated for C H O C, 75.46%; H, 8.67%. Found: C, 75.37%; H, 8.42%.

The following illustrates the use of the compounds of the invention in preparing other compounds having hormonal activity, and are exemplary of a process aspect of the invention.

EXAMPLE 14 13/3-methy1-3-methoxygona-1,3,5(10),8,14- pentaen-17-one Add 13,8 methyl 3 methoxy-S,l4-secogona-1,3,5 (10),9(11)-tetraene-14,17-one (14 g.) to a solution of anhydrous toluene-p-sulphonic acid (14 g.) in dry benzene (500 cc.). Allow the mixture to stand at room temperature for 3 hours and then add ether (100 cc.) and wash with water, aqueous sodium carbonate, brine and dry. Remove the solvent under reduced pressure and distil the red gummy residue at 230 (bath temperature) 0.2 mm. Hg. Crystallize the distillate to obtain the title product.

To obtain 13/3 ethyl 3 methoxygona-1,3,5(10),8,14- pentaen-17 one cyclize 13p ethyl-3-methoxy-8,14-secogona-1,3,5(10),9(l1)-tetraene-14,17-dione with toluene-psulphonic acidaccording to the manipulative procedure described above.

To obtain 13fi-n-propyl-3-methoxygona-1,3,5 10),8,14- pentaene 17 one cyclize 13B n-propyl-3-methoxy-8,14- secogona-1,3,5(10),9(11)-tetraene-14,17-dione with toluene-p-sulphonic acid according to the manipulative procedure described above.

To obtain 13 B-n-butyl-3-methoxygona-1,3,5 (10),8,14- pentaene 17 one cyclize 13B n butyl 3 methoxy- 8,14 secogona 1,3,5(10),9(11) tetraene 14,17 dione with toluene p sulphonic acid according to the manipulative procedure described above.

To obtain 13;? methyl 3 ethoxygona 1,3,5(10),- 8,14 pentaene l7 one cyclize 13,8 methyl 3- ethoxy 8,14 secogona 1,3,5(10),9(11) tetraene 14,- 17 dione with toluene p sulphonic acid according to the manipulative procedure described above.

To prepare 13/5 ethyl 3 ethoxygona 1,3,5(10),- 8,14 pentaene 17 one treat 1318 ethyl 3 ethoxy- 8,1,4 secogona 1,3,5(10),9(l1) tetraene 14,17 dione with toluene p sulphonic acid according to the manipulative procedure described above.

To prepare 13B n propyl 3 ethoxygona 1,3,- 5(l0),8,14 pentaene 17 one treat 13,8 n propyl- 3 ethoxy 8,14 secogona 1,3,5(10),9(11) tetraene- 14,17 dione with toluene p sulphonic acid accordirig to the manipulative procedure described above.

To prepare 13;? n butyl 3 ethoxygona- 1,3,5 10),- 8,14 pentaene 17 one treat 13B n butyl 3 ethoxy- 10 8,14 secogona -1,3,5(10),9(11) tetraene 14,17 dione with toluene 'p sulphonic acid according to the manipulative procedure described above.

To prepare 13,8 ethyl 3 hydroxygona 1,3,5(10),- 8,14 pentaene 17 one treat 13/8 ethyl 3 hydroxy- 8,14 secogona 1,3,5(10),9(11) tetraene 14,17 dione with toluene p sulphonic acid according to the manipulative procedure described above.

To prepare 13,8 ethyl 3 methoxy 6 methylgona- 1,3,5(10),8,14 pentaene 17 one treat 13;? ethyl- 3 methoxy 6 methyl 8,14 secogona l,3,5(10),9- (11) tetraene 14,17 dione with toluene p sulphonic acid according to the manipulative procedure described above.

To prepare 13 ,8 ethyl 3 methoxy 7 methylgona- 1,3,5(10),8,14 pentaene 17 one treat 13B ethyl- 3 methoxy 7 methyl 8,14 secogona 1,3,5(10),- 9(11) tetraene 14,17 dione with toluene p sulphonic. acid according to the manipu ative procedure described above.

EXAMPLE 15 l3fi-methy1-3-methoxygona-1,3,5 10) ,8,14- pentaene-17-one Dissolve 13;? methyl 3 methoxy 8,14 secogona- 1,3,5(10),9(11) tetraene 14,17 dione (0.5 g.) in methanol (15 cc.) at 40 and add 10 N hydrochloric acid until the solution becomes turbid. Allow the mixture to cool to 25 and after 1 hour filter the precipitate and recrystallize from methanol to obtain the title product (0.4 g.), M.P. 112-115; ultraviolet absorption peak at 313 mu (6 34,500).

To prepare 13B ethyl 3 methoxygona 1,3,5(10),- 8,14 pentaen 17 one cyclize 13B ethyl 3 methoxy- 8,14 secogona 1,3,5(10),9(11) tetraene 14,17- dione with hydrochloric acid according to the manipulative procedure described above.

EXAMPLE 16 13 fl-ethyl-3-methoxygona-1,3,5 10),8,14- pentaen-17-one Dissolve 13 8 ethyl 3 methoxy 8,14 secogonal,3,5(10),9(11) tetraene 14,17 dione (14.4 g.) in dry benzene (500 cc.) containing anhydrous p-toluenesulphonic acid (15 g.) and allow the mixture to stand at 25 for 3 hours. Add ether cc.) and wash the solution with water, aqueous sodium carbonate, brine and dry. Evaporate the solvent and distill the residue at 235 (bath temperature) at 0.25 mm. Recrystallize the distillate from ethanol containing a little ethyl acetate to obtain the title product (6.3 g.), M.P. 69-71 EXAMPLE l7 3-benzyloxy-13 8-methyl-8,14-secogona- 1,3,5( l0),8,14-pentaen-17-one Dissolve 3 benzyloxy methyl 8,14 secogona- 1,3,5(10),9(11) tetraen 14,17 dione (1 g.) in ethanol (10 cc.) at 60 and treat the solution with 10 N hydrochloric acid (1 cc.). After 4 minutes add water (10 cc.) and extract the mixture with cyclohexane (2 x 30 cc.). Wash, dry and evaporate the organic extracts and recrystallize the residue from cyclohexane to obtain the title compound (0.42 g.), M.P. 131-133 EXAMPLE 18 3 -benzyloxy-13 5-ethylgona-1,3,5(10),8,l4- pentaen-17-one Dissolve 3 benzyloxy 136 ethyl 8,14 secogona- 1,3,5 10 ,9(11 tetraene 14,17 dione (0.8 g.) in ethanol (10 cc.) at 60 and add 10 N hydrochloric acid (1 cc.). After 4 minutes add water (10 cc.) followed by cyclohexane (30 cc.). Separate the organic layer and extract the aqueous layer with cyclohexane (30 cc.) Wash, dry and evaporate the combine organic extracts and evaporate the solvent. Recrystallize the residue from ethanol 11 to obtain the title compound (0.371 g.), M.P. 131-134; infrared absorption peaks at 5.75, 6.25, 6.65

EXAMPLE 19 3-hydroxy-13/3-methylgona-1,3,5(10),8,14- pentaen-17-one Stir l3fl-methyl 3 tetrahydropyranyloxy 8,14- secogona 1,3,5(10),9(11) tetraene 14,17 one (1 g.) with polyphosphoric acid (10 cc.) at 60 for 15 minutes. Add water to the cooled mixture and extract with ether-ethyl acetate (1:1, 25 cc.). Wash, dry and evaporate the organic extract and wash the residue with a little ether to afford the title product (0.045 g.), M.P. 206210 (dec.); ultraviolet absorption peak at 315 mu (6 25,000).

EXAMPLE 20 3-hydroxy-13B-methylgona-l ,3,5 10) ,8,14- pentaen- 17 -one Stir 13B methyl 3 tetrahydropyranyloxy 8,14- secogona 1,3,5(l),9(11) tetraene 14,17 dione (7.1 g.) in methanol (20 cc.) with 10 N hydrochloric acid (2 cc.) for minutes at 20 and then add water (3 cc.) and cool to 0. Filter the product and Wash with aqueous methanol to obtain the title compound (3.4 g.), M.P. 216-220".

EXAMPLE 21 2,3-dimethoxy-13,8-methylgona-1,3 ,5 ,8,14- pentaen-17-one Reflux 2,3 dimethoxy 1313 methyl 8,14 secogona- 1,3,5(10),9(11) tetraene 14,17 dione (1 g.) in methanol cc.) and add 10 N hydrochloric acid until the solution lbecomes turbid. Add tetrahydrofuran dropwise until the solution is clear and reflux for 5 minutes. Cool, filter the solid, wash with methanol and recrystallize from ethanol to obtain the title compound, M.P. 137- 140.

Analysis.Calculated for C H O C, 77.39%; H, 7.11%. Found: C, 77.17%; H, 7.05%,

EXAMPLE 22 3-cyclopentyloxy-l3fl-ethylgona-l,3,5( l0) ,8, l4-

pentaen-17-one Reflux 3 cyclopentyloxy 13 ethyl 8,14 secogonal,3,5(10),9(11)-tetraene-14,17-dione (11.8 g.) in methanol (100 cc.) and 10 N hydrochloric acid (8 cc.) for 45 minutes. Add water and isolate the product with ether. Chromatograph on a column of Florisil (400 g.), eluting with benzene and recrystallize the solid fractions from ethyl acetate-methanol to obtain the title compound, 5.35 g., M.P. 93-96"; ultraviolet absorption peak at 313 mu EXAMPLE 23 13 S-ethyl-3-methoxy-7-methy1gona 1,3,5 10) ,8,14-pentaen-17-one Stir 13/8 ethyl 3 methoxy-7-methyl-8,14-secogona- 1,3,5(l0),9(1l)-tetraene-14,17-dione (1 g.) in benzene (50 cc.) containing anhydrous p-toluenesulphonic acid (0.5 g.) for 2 hours at Cool the mixture, filter, and wash, dry and evaporate the residue to obtain the title compound as a gum (0.8 g.); ultraviolet absorption peak at 313 m (6 28,600).

EXAMPLE 24 l3/3-ethyl-3-hydroxygona-1,3,5(10),8,14- pentaen-17-one Stir 13,8-ethyl-3-hydroxygona-1,3,5 10) ,8,14-secogonal,3,5(10),9(11)-tetraene (50 g.) in methnaol (150 cc.) with 10 N hydrochloric acid (15 cc.) for 10 minutes. Add a little water, cool to 0 and filter. Recrystallize the residue from methanol to give the title compounds (39.7 g.), M.P. 160162.

12 EXAMPLE 25 13,8-ethylgona-1,3,5(10),8,14-pentaene-17-one EXAMPLE 26 13,8-ethyl-3-methoxygona-1,3,5(10),8,14,16- hexaen-17-ol, acetate Reflux 13 ethyl-3-methoxy-8,14-secogona-l,3,5(10),9- (11)-tetraene-14,17-dione (1.5 g.) with isopropenyl acetate (25 cc.) and toluene-p-sulfonic acid (0.25 g.) for 4 hours with distillation of ca. 10 cc. of the solvent.'Cool, dilute with ether and Wash, dry and evaporate the organic solution. Filter the solid residue through a short column of Florisil and recrystallize the product from ethanolhexane to give the title compound, M.P. 119120.

EXAMPLE 27 17-ethoxy-13B-ethyl-3-methoxygonal,3,5( 10),8,14,16-hcxaer1e Dissolve l3-ethyl-3-methoxy-8,l4-secogona-1,3,5( l0) 9(11)-tetraen-14,17-dione (1 g.) in ethanol (4 cc.) and ethyl orthoformate (1 cc.), add concentrated sulfuric acid (1 drop) and keep the mixture at 45 for /2 hour. Add ethyl orthoformate (0.5 cc.) and keep the mixture at 55 for a further /2 hour. Pour the cooled mixture into saturated aqueous sodium hydrogen carbonate and isolate the product with ether. Filter the product through a column of Florisil with hexane containing 10% benzene and evaporate the eluate and recrystallize from ethanol to obtain the title compound, M.P. 7880; ultraviolet absorption at 353 m (6 25,000).

The subject matter which the applicants regard as their invention is particularly pointed out and distinctly claimed as follows:

1. A secogonane of the formula:

0 R II "E wherein X is a 2-(1,2,3,4-tetrahydro-l-naphthylidene)- ethyl group instituted in the 2-position of the naphthylidene ring and R is alkyl of 1 to 18 carbon atoms.

2. 3 alkoxy- 13-ethyl-8,14-secogona-l,3,5(l0),9(11)- tetraene-14,17-dione.

3. 3 methoxy-13-ethyl-8,14-secogona-l,3,5(10),9(11)- tetraene-14, l7-dione.

4. 3 methoxy 13-rnethyl-8,14-secogona-l,3,5(l0), 9(11)-tetraen-14,17-dione.

5. A process for preparing a compound with an 8,14- secogona 1,3,5(10),9(ll)-tetraene-14,17-dione nucleus substituted in the l3-position with a polycarbon-alkyl radical comprising condensing a compound having a 1- vinyl-l-tetralol nucleus with a compound having a 1,3- cyclopentanedione nucleus substituted in the 2-position with a polycarbon-alkyl radical under Michael condensation conditions.

6. A process for preparing a compound with a 13- methyl 8,14 secogona-l,3,5(10),9(11)-tetraene-14,l7- dione nucleus comprising condensing a compound having a l-vinyl-l-tetralol nucleus with a compound having a 2- methyl-l,3-cyclopentanedione nucleus under Michael reaction conditions.

13 7. A compound of the formula wherein R is lower alkyl and R is lower alkyl.

US. Cl. X.R. 

